Neurotrophins, such as NGF and BDNF, are prominent regulators of neuronal survival, growth and differentiation during development of the vertebrate nervous system. The actions of neurotrophins are dictated by two classes of cell surface receptors, the Trk receptor tyrosine kinases and the p75 neurotrophin receptor. After binding, neurotrophins and each of their receptors undergo internalization, intracellular trafficking and transport. In the last grant period, we studied the activation of Trk receptor tyrosine kinases via a G protein-coupled receptors (GPCR). Two GPCR ligands, adenosine and pituitary adenylate cydaseactivating polypeptide (PACAP), can activate Trk receptor activity to increase the survival of neural cells in the absence of neurotrophins. In contrast to neurotrophin treatment, the majority of activated Trk receptors were found in intracellular locations, such as Golgi and endosomal membranes. These results indicate that intracel lular trafficking of receptors plays an important role in their signaling outcomes. In the next grant period, we will test the hypothesis that proteins that regulate Trk receptor internalization, translocation and recycling are critical to our understanding of neurotrophin signaling. Both the biosynthetic and the endocytic pathways will be examined for their impact on Trk activity. Because the localization of neurotrophin receptors is critical to neuronal cell survival and plasticity, our investigation is directly relevant to the understanding and treatment of neurodegenerative diseases, such as amyotrophic lateral sclerosis, Huntington's and Alzheimer's diseases.